Obesity and overweight have become a major health threat in humans with an immense impact to public health. Obesity and overweight pose a major risk for serious chronic diseases, including type II diabetes, cardiovascular disease, dyslipidemia, sleep apnea, hypertension and stroke, and certain forms of cancer. The risk of comorbidities of obesity, including mortality, increase with increasing body mass index (BMI). Obesity is also associated with serious social and psychological aspects, affecting virtually all ages and socioeconomic groups.
According to certain publications, obesity may be divided into two types, obesity with binge eating disorder (BED) and obesity without BED, since BED appears to represent a distinct familial phenotype in obese individuals (e.g. Hudson et al. Arch Gen Psychiatry. 2006, 63(3):313-9).
Drugs prescribed for obesity may reduce fat absorption or regulate satiety via their action on serotonergic, norepinephric, dopaminergic or the cannabinoid receptor systems in the brain (e.g. Jimerson et al., Arch. Gen. Psychiatry, 49:132-138, 1992). The effects of the sympathetic nervous system (SNS) on metabolism were shown to be associated with development and maintenance of obesity, and accordingly, the SNS has been suggested as a potential therapeutic target in the treatment of obesity (e.g. Snitker et al. Obes Rev. 2000,1(1):5-15).
Reboxetine is a norepinephric reuptake inhibitor (NRI) used in the treatment of acute depression, panic disorder and attention-deficit/hyperactivity disorder (ADHD). Obese patients with BED treated with 8 mg/day of reboxetine for 12 days, showed reduced binge eating behavior (Silverio et al. Eat Weight Disord. 2005, 10(4):e93-6). It has also been disclosed that coadministering reboxetine (4 mg/day) with the atypical antipsychotic olanzapine, reduced the weight-gain associated with olanzapine administration (Poyurovski. Psychopharmacology (Berl), 2007, 192(3):441-8).
Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) mostly prescribed as an anti-depressant and also used for the treatment of obsessive compulsive disorder and bulimia nervosa. Fluoxetine, administered at a dose of 60 mg/day, showed statistically significant weight loss compared to placebo following 28 weeks of treatment. However, at the end of the study (at week 52) no difference between treatment and placebo groups was observed (Goldstein et al. Int J Obes Relat Metab Disord. 1994, 18(3):129-35).
Combinations of SSRIs and NRIs for treating indications other than eating disorders are known. For example, U.S. Patent Application No. 2005/0059715 discloses a combination therapy for the treatment of pain comprising a synergistic amount of an alpha-2-delta ligand and a dual serotonin norepinephrine reuptake inhibitor or one or both of an SSRI and an NRI, or pharmaceutically acceptable salts thereof.
A combination of SSRIs, including fluoxetine, and NRIs, including reboxetine, for treating and preventing an extensive list of disorders, eating disorders among others, is disclosed in U.S. Patent Application, Publication No. 2005/0014848. It is further discloses that the SSRI and the NRI may be administered in one or more unit doses each comprising 1 to 300 mg of the active component, but does not specify any preferred amounts or ratios between said components.
U.S. Patent Application, Publication No. 2007/0275970, discloses a method for affecting weight loss, comprising administering an opioid antagonist together with a second compound, such as, a combination of an SSRI and an NRI.
PCT Publication No. WO 2009/035473 discloses a method of treating binge eating disorder or obesity resulting from binge eating behavior, comprising providing an effective amount of amphetamine prodrug, methylphenidate prodrug, or methylphenidate analog to a patient, as the only active agent or together with one or more additional active agents, including antidepressants such as SSRIs and NRIs.
There is a recognized medical need for an effective and specific treatment of obesity.